No Guts, No Glory: How Microbiome Research is Changing Medicine

Experts think the microbiome could be the key to treat all sorts of diseases. But how can we make these microorganisms collaborate with us? Let’s do a gut check.

We’ve all been told that our DNA is what makes us what we are. What many don’t realize is that the DNA that defines us is not just that of our own human cells, but also that of the millions of microbes that live on our skin, inside our gut and pretty much everywhere in our body. In terms of the total number of unique genes, it is estimated that the community of microorganisms that share our body outnumbers our own genes by 150 times. Thus, some scientists refer to them as our “second genome,” and some even treat it as one more of our organs.

With the advent of DNA sequencing technologies, scientists started to study in depth the role that these microbes play in our lives, and we can no longer deny that they are essential to our health. In the last decade, the number of scientific publications on the topic has exploded. And over 800 registered clinical trials are testing whether these tiny creatures can help us treat human diseases ranging from inflammatory bowel disease to diabetes, autism, cancer, and AIDS.

The expectations are certainly high, with the human microbiome market projected to reach a whopping $3.2Bn by 2024. Others have a gut feeling that its impact on medicine will not be as big, though. So I set out to review what’s going on in the field and whether studying our tiny life partners can really help us cure human diseases. But let’s start from the beginning.

What is the microbiome?

The term microbiome was coined by Nobel Laureate Joshua Lederberg. He describes it as “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space and have been all but ignored as determinants of health and disease.”

We acquire our first microbes at birth as we leave the sterile conditions of the womb. After that, scientists believe that our first 3 to 5 years of life are essential to establish the microbiome, whose composition is unique to each person and changes through life as does our environment. The factors that can influence the microbiome composition are many, from diet — for example, vegans and vegetarians have distinct microbes — to exercise habits, age, location and many more we might still not know of.

But most importantly, dysbiosis — an unbalanced microbiome composition — has been linked to inflammatory bowel disease (IBD), multiple sclerosis, diabetes, allergies, asthma, autism, and many other conditions.

To better understand these links, many projects launched in the past few years have focused on mapping microbial genes that are associated with disease. In Europe, the MetaHIT project has looked at IBD and obesity, while in the US the Human Microbiome Project focuses on studying preterm birth complications and diabetes as well as IBD.

Another indication where the microbiome could have a huge impact is cancer. It is already known that some microorganisms render cancer drugs ineffective, whereas others are actually necessary to make these drugs work. Meaning that making a patient have the right microbiome might massively affect their chances of survivingcancer.

“2018 will be the biggest clinical year in microbiome oncology,” says Isabelle de Cremoux, CEO of the VC firm Seventure — the first to have the guts to ever set up a fund dedicated exclusively to microbiome-based therapeutics. De Cremoux expects to see the results of the first in-human clinical trials this year, which could lead the way of a big wave of new therapies trying to harness the power of the microbiome.

How do we treat the microbiome?

Some of the first attempts at modifying the microbiome composition can be traced back to China thousands of years ago, where doctors treated diarrhea with so-called yellow soup — basically dried stool from a healthy person. Today, the practice is known as fecal microbiota transplant (FMT) and is delivered in the more pleasant form of frozen capsules. In France, MaaT Pharma is using this technique to help patients recover from leukemia and joint infections after their microbiome has been wiped due to intensive chemotherapy and antibiotic treatments. In the US, Rebiotix uses FMT to fight C. difficile infections and ulcerative colitis.

But transplanting whole microbiomes can be quite a crude approach. Others are inclined towards a more defined approach where specific bacterial strains or a defined consortium — a group of strains — that are known to be beneficial are delivered, alive, to the patient’s gut.

In the UK, a young company called Microbiotica transfers non-pathogenic strains of C. difficile to fight C. difficile infections as well as IBD and cancer. The firm has set out to rival the likes of US-based Seres Therapeutics, one of the most advanced microbiome companies despite a big setback over a year ago, and Vedanta, which is partnered with Janssen to treat IBD through the microbiome.

These approaches have drawn a lot of attention to the field, but some are skeptical of their real value. Some scientists argue that the bacteria we ingest are not as well adapted to living in our gut as those that have been living there for years, therefore flushing out rapidly and failing to exert a significant change in our health.

“If you look back to over 50 years of clinical research on probiotics, there is no demonstration of clinical efficacy of live bacteria,”Pierre Belichard, CEO of Enterome, told me bluntly.

Based in Paris, Enterome follows a sort of inverse approach to live therapeutics. Instead of adding benefitial bacteria to the microbiome, its goal is to develop drugs that specifically target bacteria that cause disease while leaving the rest of the microbiome intact. The company’s most advanced program is aimed at treating Crohn’s disease, while a second candidate targets cancer and has attracted a partnership with Bristol-Myers Squibb.

Other companies following a similar approach of selectively drugging pathogenic microbes are Second Genome and C3J Therapeutics in the US and Infant Bacterial Therapeutics in Sweden.

Meanwhile, rather than using drugs, others make use of a type of viruses aptly termed bacteriophages that have evolved over millions of years to only infect and kill very specific strains of bacteria. That is the case of EpiBiome in the US or BiomX in Israel.

The French startup Eligo Bioscience takes this concept a step further by using these bacteriophages to deliver the gene editing tool CRISPR/Cas9 into the bacteria. Once inside, CRISPR is able to kill the bacteria by cutting their DNA, only when a specific DNA sequence is present in the microorganism. Thus, even within the same bacterial strain, only those that carry a gene that causes disease are eliminated.

Finally, certain companies engineer bacteria to make them produce drugs directly within the gut. Among them are Blue Turtle Bio and Synlogic in the US, and Anaero Pharma in Japan. The approaches seem limitless, and we will certainly see more and more coming up in following years.

What’s on the horizon?

As researchers work their guts out to unveil the multiple links between the microbiome and our health, we’ll certainly see more and more companies trying to exploit them. And with microbiome treatments will also come microbiome diagnostics to determine which patients can benefit from these therapies. However, we must not forget that this is still a rather new field. So far there are only 6 microbiome biotechs that have made it to the public market, and there have been no exits to convince investors that it is a viable business — though big pharma have started buying their way in. “We are just taking the first steps into an area that will revolutionize our concept of health and medicine,” says David Kyle from US-based Evolve Biosystems.

This means that, very likely, a high number of approaches will fail to treat disease. But that is normal for every new medical technology. From all the areas where we now think the microbiome could make a difference, we might find that some are more challenging to treat through the microbiome. So far, gut infections and inflammatory diseases seem to be strongly correlated to the gut microbiota, whereas HIV infections, mental conditions and aging seem to have a weaker link to our microbiome. And, in many cases it is still to be determined whether an altered microbiome is the cause or the effect of a disease — or both.

A crucial challenge for the field will be to move from correlation to causation, and a lot of research is still needed for that. “The microbiome is a really complex field, and although there is a consortium that includes hundreds of different types of bacteria, every person has their own set,” admits Henry Raths, VP of BD at Seres Therapeutics.

Despite his huge experience with microbiome companies, Rath is still concerned about regulations for the development of microbiome-derived products. “There is not a well-established protocol for FDA approval when it comes to the microbiome,” he explains.

But, as investment grows and VC firms like Seventure in France and Flagship Pioneering in the US keep putting money into the field, researchers will be able to tackle the obstacles. And the public seem very keen on the topic; Companies like the British Map My Gut or the Israeli DayTwo are offering kits that anyone can use to test their microbiome’s composition and get personalized diet recommendations.

There will certainly be many ups and downs as the microbiome field establishes itself, but my gut tells me that it will defintiely bring very exciting solutions to many medical challenges. I just can’t wait to see the many unexpected ways the microbes that share our body can make our lives better.